Our team of writers are reporting live from Athens and have picked key notes from Day 2 - use the links to skip to the sections below, or scroll to view the full summary.
Ahead of the spinal muscular atrophy (SMA) Learning Zone coming soon to epgonline.org, here is a short refresher. SMA is caused by the loss of the SMN1 gene and characterised by progressive muscle weakness and loss of motor function, with the severity inversely correlated to the copy number of SMN2. The SMN2 gene is identical to SMN1 except for a point mutation that leads to exclusion of exon 7 in ~90% of the protein produced. The shortened SMN2 isoform is non-functional and quickly degraded. In general, the protein produced from two functional SMN2 copies is not sufficient to compensate for the loss of SMN1 and these patients are likely to have severe type 1 SMA. However, the SMN2 copy number is variable in the population and SMA patients with three or more copies of SMN2 are likely to suffer from a less severe form of the disease.
Nusinersen is an antisense oligonucleotide therapy that increases the inclusion of exon 7 in SMN2 transcripts. It is the first and only disease-modifying treatment for SMA currently approved by the EMA. The amount of interest in nusinersen was evident from the participation in the ‘Time is motor neuron in SMA’ symposium where the room was packed with many forced to stand.
To start off, Professor Enrico Bertini discussed the latest interim results from the NURTURE (NCT02386553) phase 2 trial in presymptomatic infants. All 25 trial participants (15 with two and 10 with three SMN2 copies) have been followed for more than two years, with half having received nusinersen for more than three years. All patients are still alive and without the need for permanent ventilation, though four patients with two SMN2 copies required short term respiratory intervention. The majority of treated patients achieved motor milestones within the normal time window. For example, 92% can walk with and 88% without assistance. None of the patients with three SMN2 copies require tube feeding at any time and only three with two SMN2 copies do sometimes, or all of the time. At two years of age, 76% had achieved maximum Hammersmith Infant Neuromuscular Examination (HINE) Section 2 (HINE-2) total scores. More detail can be found in the just published paper by De Vivo et al., 2019.
It is clear from these (and other results discussed below) that early treatment results in significantly better outcomes. Early diagnosis is therefore essential, but currently there are significant delays between disease onset and diagnosis. If you suspect it could be SMA, initiate genetic testing immediately using the SMN1/SMN2 test in preference to a neuromuscular panel. Newborn SMA screening programs are being set up in several countries, but these do raise the question of what to do about patients with four copies of SMN2 – treat or watch and wait? A potential prognostic biomarker that could predict future outcomes would be helpful in clinical practice since the SMN2 copy number does not directly translate to disease subtype. As Professor Basil Darras explained, a promising candidate is phosphorylated heavy neurofilament (pNF-H) which is released into the cerebrospinal fluid and blood following axonal damage or neuronal degeneration. This is extremely high in SMA, especially in presymptomatic patients, but rapidly reduced with nusinersen treatment, though levels are still higher than normal. This may mean that neurodegeneration is still ongoing even with treatment and that combination treatment with other new therapies might be necessary. Coincidentally, a new phase 2/3 dose-escalating trial (NCT04089566) to evaluate the potential for even greater efficacy with higher doses of nusinersen was announced today (see here).
Of course, the continued survival of treated SMA patients will lead to new challenges. Professor Francesco Muntoni discussed how SMA disease modifying treatments will change the prevalence. Although patients will live longer, require fewer hospitalisations and have less complications, they will still require standard of care. For example, scoliosis has not been a problem in type 1 patients as they were unable to sit or walk, but in future this will be increasing. Bone health of treated patients needs be looked at as poor condition prevents scoliosis treatment. Optimal pulmonary management will still be necessary. The symposium talks were interspersed with videos of patients showing truly impressive progress considering that patients would never achieve these motor milestones without treatment.
Later, Professor Darras presented more details on the ‘Longer-term assessment of Nusinersen treatment in children with later onset spinal muscular atrophy who enrolled in CS2/CS12: an interim analysis of the SHINE Study’ (NCT02594124). These are 24 patients which have been on nusinersen treatment for 6 years (10 type 2 and 14 type 3; age 7–21 at last visit). Type 2 patients showed clinically meaningful improvement in the Hammersmith Functional Motor Scale–Expanded (HFMSE) of 9.0 points, a change in Upper Limb Module (ULM) of 3.9 points. Type 3 patients increased their distance in the Six-Minute Walk Test (6MWT) by 98.1 meters and had stable HFMSE scores. Clearly, treatment of older patients still yields results and these mean real improvements in quality of life for patients.
Quality of life (QoL) was also a topic in the very moving symposium ‘Rewriting the tale of Sisyphus: the SMA boulder that went up a mountain and came down to change a disease’ chaired by Edward Ndopu. Following the theme of the symposium, Mr Ndopu told us about the boulders he has to push up the mountain every day. Simple things that the able bodied take for granted like going to the toilet while enjoying a night out with friends can be such a boulder, while raising £85,000 on top of a full scholarship to Oxford University to pay for necessary round-the-clock care surely counts as a mountain in itself. Professor Muntoni then presented some background on SMA and the current patient journey as well as possible future changes. He highlighted results in preclinical models that increasing SMN protein in peripheral tissues is necessary for long term rescue in severe disease. This was followed by a brief discussion of the FIREFISH (NCT02913482), SUNFISH (NCT02908685) and JEWELFISH (NCT03032172) studies of risdiplam which showed a consistent twofold increase in SMN protein even in patients already on nusinersen or other treatments. Professor Eugenio Mercuri also discussed QoL and how disease symptoms can impact emotional and social aspects of life for individuals with SMA. Even small motor function improvements may make a real difference in these aspects not just for the patient themselves but also for their families and carers. He closed with a look ahead. There will be increased resource demands as prevalence and therefore care and enablement needs increase. New interventions may be needed as disease outcomes of treated SMA may be different from the traditional SMA types. The symposium finished with an interesting discussion on all these issues.
Although there was one talk on the SMA gene therapy onasemnogene abeparvovec (Zolgensma®) today, there is much more on gene therapy to come tomorrow, so we will include it in tomorrow’s roundup.
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Tune in for more from the EPNS Congress 2019 tomorrow.
The EPNS Congress 2019 is the place to be this week for all that is happening in paediatric neurology. We look ahead to the highlights in neuromuscular disorder research that the epgonline.org team will be reporting on.
Even more on gene therapy today – see the new data from the SPR1NT and STR1VE-EU studies in spinal muscular atrophy and a thought-provoking discussion of the ethical dilemmas associated with gene therapy trials. What are the adverse events seen with gene therapy and how will next generation sequencing change your medical practice?
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